Chromogranin A: nicotinic signaling and desensitization. Nicotine is a component of tobacco that motivates continued abuse despite harmful effects. Catecholamine release from catecholaminergic cells is triggered by nicotinic cholinergic stimulation, prompting exocytotic co-release of storage vesicle constituents: catecholamines, neuropeptides, and acidic chromogranins, the major component being chromogranin A (CgA). CgA is cleaved to biologically active peptides, such as a novel fragment (CgA344-364, which we discovered and named "catestatin") that feedback-inhibits catecholamine release. We found that stimulation of neuronal nicotinic receptors causes secretion of catecholamines and CgA, transcriptionally upregulates the biosynthesis of CgA and catecholamines, and desensitizes (creates tolerance to) further nicotinic responses, both secretory and transcriptional. In preliminary studies, we found that catestatin antagonized all of these cholinergic responses. Thus, CgA (and its fragment catestatin) seem to play a central role in neuronal nicotinic cholinergic signaling, both in responding positively to nicotine (in secretion and transcription), and in blocking all known stimulatory (secretory or transcriptional) or desensitizing action of nicotine. These features of CgA's and catestatin's responses and action suggest a homeostatic, negative feedback role. Here we will explore these functions of CgA and catestatin, using cultured chromaffin cells. Two general areas will be characterized. I. Effects of nicotinic cholinergic stimulation to cause secretion (of catecholamines and CgA), CgA biosynthesis, and desensitization of (tolerance to) further secretion or transcriptional responses to nicotine. We have already characterized CgA promoter domains (in cis) which mediate the response to nicotine, and have begun to establish signal transduction pathways involved in transcription and its desensitization. II. Catestatin's antagonism of nicotinic responses (secretion, transcription, and desensitization thereof). We characterized catestatin's inhibitory effects on secretion, specifically as a non-competitive nicotinic cholinergic antagonist, and established its effect on nicotinic signal transduction, as well as protection against prior nicotinic desensitization. These studies may establish a novel homeostatic (negative feedback) mechanism by which an endogenous peptide antagonizes nicotinic stimulation of catecholamine release, CgA gene transcription, and desensitization of both secretion and transcription. Such protection against desensitization may be advantageous to an organism during circumstances of prolonged stress, perhaps guarding against premature termination of secretory and transcriptional responses to physiological nicotinic stimulation.